Transient receptor potential melastatin 8 ion channel in macrophages modulates colitis through a balance-shift in TNF-alpha and interleukin-10 production.

The transient receptor potential (TRP) ion channel family is well characterized in sensory neurons; however, little is known about its role in the immune system. Here we show that the cold-sensing TRPM8 has an unexpected role in innate immunity. TRPM8 expression and function in macrophages were demonstrated in vitro using molecular techniques and calcium imaging. In addition, adoptive macrophage transfer and systemic interleukin (IL)-10 overexpression were performed in experimental colitis. TRPM8 activation induced calcium-transients in murine peritoneal macrophages (PM) and bone marrow-derived macrophages of wild-type (WT) but not TRPM8-deficient mice. TRPM8-deficient PM exhibited defective phagocytosis and increased motility compared with those in WT, whereas the opposite effects of TRPM8 activation were induced in WT PM. TRPM8 activation or blockage/genetic deletion induced a anti- or pro-inflammatory macrophage cytokine profile, respectively. WT mice treated with repeated menthol (TRPM8 agonist) enemas were consistently protected from experimental colitis, whereas TRPM8-deficient mice showed increased colitis susceptibility. Adoptive transfer of TRPM8-deficient macrophages aggravated colitis, whereas systemic IL-10 overexpression rescued this phenotype. TRPM8 activation in peptidergic sensory neurons did not affect neuropeptide release from the inflamed colon. TRPM8 in macrophages determines pro- or anti-inflammatory actions by regulating tumor necrosis factor-α and interleukin-10 production. These findings suggest novel TRPM8-based options for immunomodulatory intervention.

[Percutaneous coronary intervention in a patient with acute myeloid leukemia]. / Koronarintervention bei einer Patientin mit akuter myeloischer Leukämie.

HISTORY AND ADMISSION FINDINGS: A 63-year-old woman was referred to our hospital for evaluation of leukocytopenia and blast cells in the peripheral blood smear. The general condition was reduced, a maculo-papulous exanthema of the face and upper body as well as a general lymphadenopathy were found. INVESTIGATIONS: Bone marrow examination revealed the diagnosis of acute myeloid leukemia (AML) FAB M1 and a normal karyotype. Extramedullary manifestations of AML were demonstrated in skin and lymphnode biopsies. ECG showed no signs of ischemia, echocardiography a normal left-ventricular function. TREATMENT AND COURSE: The patient received induction treatment using sequential high-dose cytosinarabinosid and mitoxantrone, which rapidly resolved the extramedullary skin- and lymphnode-manifestations of the AML. During the chemotherapy-associated bone marrow aplasia a non-ST-elevation infarction (NSTEMI) developed combined with severe ischemic cardiomyopathy, high-grade mitral valve deficiency and serious congestive heart failure with respiratory failure. Coronary artery angiography showed a complete occlusion of the proximal ramus circumflexus. Percutanous coronary intervention (PCI) with implantation of a bare-metal stent was performed, which resulted in prompt improvement of the condition. Despite the transfusion-dependent thrombocytopenia a dual antiplatelet therapy with acetylsalicylic acid and clopidogrel was given. After each unit of platelets transfused a loading dose of 600 mg clopidogrel was given to prevent stent thrombosis. The patient did not experience major bleeding and was discharged in complete remission of AML and completely cardially recompensated. CONCLUSION: Coronary angiography and stenting can generally be safely performed in patients with transfusion-dependent thrombocytopenia. Despite a higher risk of bleeding an oral dual antiplatelet therapy with aspirin and e. g. clopidogrel according to the guidelines should be performed, but its duration should be adapted to the individual patient circumstances.

Effects of intraperitoneal mitomycin C adsorbed on activated carbon on adhesion formation and mesothelial cells in vitro.

OBJECTIVE: To investigate the incidence of adhesions after intraperitoneal instillation of mitomycin C adsorbed on activated carbon (MMC-CH). DESIGN: Animal and laboratory studies. SETTING: University hospital, Germany. ANIMALS: 90 Sprague-Dawley rats. INTERVENTIONS: Laparotomy, small bowel anastomosis, and intraperitoneal instillation of saline (controls, n = 27), activated carbon alone (n = 24) or MMC-CH (n = 26). Cultures of monolayers of human mesothelial cells. MAIN OUTCOME MEASURES: Measurements of adhesions by planimetry. Toxicity of mitomycin C alone and charcoal alone in mesothelial cell monolayers as reflected by cell proliferation and measurement of lactate dehydrogenase activity. Concentrations of plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) as measures of the fibrinolytic activity of mesothelial cells. RESULTS: Both activated carbon and MMC-CH caused a significant increase of adhesion formation in rats. Activated carbon also reduced the fibrinolytic activity of mesothelial cells, and mitomycin C caused concentration-dependent cytotoxicity in vitro. CONCLUSIONS: Activated carbon combined with high concentrations of mitomycin C may cause intraperitoneal infective complications by increasing the rate of adhesion formation and reducing the fibrinolytic activity of mesothelial cells. We recommend a new absorbable carrier for intraperitoneal chemotherapy.